Unknown

Dataset Information

0

Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors.

ABSTRACT: The peroxisome proliferator-activated receptors (PPARs) are transcriptional regulators of glucose, lipid, and cholesterol metabolism. We report the x-ray crystal structure of the ligand binding domain of PPAR alpha (NR1C1) as a complex with the agonist ligand GW409544 and a coactivator motif from the steroid receptor coactivator 1. Through comparison of the crystal structures of the ligand binding domains of the three human PPARs, we have identified molecular determinants of subtype selectivity. A single amino acid, which is tyrosine in PPAR alpha and histidine in PPAR gamma, imparts subtype selectivity for both thiazolidinedione and nonthiazolidinedione ligands. The availability of high-resolution cocrystal structures of the three PPAR subtypes will aid the design of drugs for the treatments of metabolic and cardiovascular diseases.

SUBMITTER: Xu HE 

PROVIDER: S-EPMC61142 | biostudies-literature | 2001 Nov

REPOSITORIES: biostudies-literature

Json Xml
altmetric image

Publications

Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors.

Xu H E HE   Lambert M H MH   Montana V G VG   Plunket K D KD   Moore L B LB   Collins J L JL   Oplinger J A JA   Kliewer S A SA   Gampe R T RT   McKee D D DD   Moore J T JT   Willson T M TM  

Proceedings of the National Academy of Sciences of the United States of America 20011106 24

The peroxisome proliferator-activated receptors (PPARs) are transcriptional regulators of glucose, lipid, and cholesterol metabolism. We report the x-ray crystal structure of the ligand binding domain of PPAR alpha (NR1C1) as a complex with the agonist ligand GW409544 and a coactivator motif from the steroid receptor coactivator 1. Through comparison of the crystal structures of the ligand binding domains of the three human PPARs, we have identified molecular determinants of subtype selectivity.  ...[more]

Similar Datasets

Unknown Structural insights into human peroxisome proliferator activated receptor delta (PPAR-delta) selective ligand binding.
| S-EPMC3350516 | biostudies-literature
Unknown Structural and biochemical basis for the binding selectivity of peroxisome proliferator-activated receptor gamma to PGC-1alpha.
| S-EPMC2441548 | biostudies-literature
Unknown Monitoring Solution Structures of Peroxisome Proliferator-Activated Receptor ?/? upon Ligand Binding.
| S-EPMC4798536 | biostudies-literature
Unknown Divergence between human and murine peroxisome proliferator-activated receptor alpha ligand specificities.
| S-EPMC3735934 | biostudies-literature
Unknown Structural Biology-Based Exploration of Subtype-Selective Agonists for Peroxisome Proliferator-Activated Receptors.
| S-EPMC8430769 | biostudies-literature
Unknown Peroxisome proliferator-activated receptors in HCV-related infection.
| S-EPMC2662434 | biostudies-literature
Unknown Peroxisome proliferator-activated receptors as therapeutic target for cancer.
| S-EPMC10902584 | biostudies-literature
Unknown Peroxisome Proliferator-Activated Receptors and the Hallmarks of Cancer.
| S-EPMC9368267 | biostudies-literature
Unknown Identification and mechanism of 10-carbon fatty acid as modulating ligand of peroxisome proliferator-activated receptors.
| S-EPMC3249069 | biostudies-literature
Unknown A functional peroxisome proliferator-activated receptor-gamma ligand-binding domain is not required for adipogenesis.
| S-EPMC2529017 | biostudies-literature